Cross-Coupling of Cyclopropyl- and Cyclobutyltrifluoroborate with Aryl- and Heteroaryl Chlorides

Abstract

Suitable conditions were found for the Suzuki-Miyaura cross-coupling reaction of potassium cyclopropyl- and cyclobutyltrifluoroborates with aryl chlorides. Both of these secondary alkyl trifluoroborates coupled in moderate to excellent yield with electron rich, electron poor and hindered aryl chlorides to give a variety of substituted aryl cyclopropanes and -cyclobutanes.

Introduction

The development of mild methods for the incorporation of the cyclopropyl group into complex molecules is becoming increasingly important due to the prevalence of cyclopropanes in natural products¹ as well as in pharmaceutical targets, where the group’s distinctive steric and electronic properties create unique opportunities for interrogating biological receptors.² The ease of access to cyclopropylborons, combined with the mild reaction conditions and tolerance of diverse functional groups, make the Suzuki-Miyaura cross-coupling³ an extremely attractive method for the installation of the cyclopropyl group into aromatic and heteroaromatic systems. To date, the majority of investigations employing the Suzuki-Miyaura reaction in this endeavor have focused on the use of cyclopropylboronic acid.⁴ Most of these reports feature aryl bromide or -iodide electrophiles as opposed to the less expensive and more readily available (albeit less reactive) aryl chlorides. The few examples using aryl chlorides are limited to activated, electron poor arenes,^4a,5 and although a number of heteroaryl triflates have been successfully cross-coupled with cyclopropylboronic acid,⁶ only one example of a heteroaryl chloride exists in the literature.^4a Furthermore, boronic acids themselves suffer from several notable drawbacks. Most significantly, the propensity of cyclopropylboronic acid to protodeboronate renders it unstable and unsafe upon prolonged storage and requires the use of between 10 and 200% excess⁴ in cross-coupling reactions. Consequently, a significant quantity of the key reagent is wasted.

Potassium organotrifluoroborates⁷ have proven to be a particularly useful class of boron reagents that are air- and moisture stable, atom economical, and resistant to protodeboronation,⁸ thereby allowing essentially stoichiometric quantities of reagent to be used in cross-coupling protocols. Organotrifluoroborates are readily accessible from diverse organoboron precursors, and in accord with this, numerous methods have been developed for their synthesis, including cyclopropanation of alkenylboronic acids or -boronate esters,⁹ transmetalation from cyclopropylzinc reagents¹⁰ and hydroboration of cyclopropenes.¹¹ Furthermore, the use of chiral boronates^9b or catalytic asymmetric hydroboration¹¹ generates enantioenriched cyclopropyl boron reagents that undergo cross-coupling with retention of configuration^9–11 to allow facile, stereospecific incorporation of substituted cyclopropanes into complex molecules. Various cyclopropyltrifluoroborates have been demonstrated to cross-couple stereospecifically to aryl bromides or iodides,^9a,10 but the use of trifluoroborates with aryl chlorides has not been investigated. The current contribution represents an expansion of the utility of the Suzuki-Miyaura reaction for the installation of the cyclopropyl unit into a wide variety of aromatic substrates using potassium organotrifluoroborates, employing both aryl- and heteroaryl chlorides.

The increased sp³ character in the carbon-boron bond of cyclobutyl organometallics, combined with the potential intrusion of a β-hydride elimination from the diorganopalladium intermediate, makes the use of cyclobutyl derivatives in cross-coupling reactions significantly more challenging than that of their cyclopropyl counterparts. In a continued effort to expand the feasibility of secondary alkyl cross-coupling reactions with potassium organotrifluoroborates,¹² we synthesized cyclobutyltrifluoroborate and examined its reaction with various aryl chlorides and report what is, to the best of our knowledge, the first example of a cross-coupling reaction using a cyclobutyl organometallic coupling partner.

Results and Discussion

Our study began with optimization of reaction conditions for the cross-coupling of aryl chlorides with commercially available potassium cyclopropyltrifluoroborate. Previous cross-coupling studies of cyclopropyltrifluoroborates with aryl bromides by Deng and coworkers^9a utilized traditional catalyst systems such as PdCl₂(dppf) or Pd(PPh₃)₄ to good effect (eq 1).

(1)

However, the former conditions proved unsuccessful in our case owing to the increased difficulty of oxidative addition to aryl chlorides.¹³ Table 1 summarizes our studies toward optimizing reaction conditions for this reaction. Previous success with dialkylbiaryl phosphine ligands in challenging systems^7,13b led us quickly to examine the Buchwald palette of phosphines. A hindered isonitrile was examined as a unique potential alternative.

Table 1.

Optimization of Reaction Conditions for Aryl Chlorides

entry	catalyst/ligand (mol %)	R	base	solvent (°C)	ratio P/SMa
1	PdCl2 (dppf).CH2Cl2 (3)	4-CN	Cs2CO3	THF/H2O (80)	5/95
2	Pd(OAc)2/XPhos (3/6)	4-CN	Cs2CO3	THF/H2O (80)	99/1
3	Pd(OAc)2/XPhos (3/6)	4-CN	K2CO3	THF/H2O (80)	100/0
4	Pd(OAc)2/XPhos (3/6)	4-OMe	K2CO3	THF/H2O (80)	78/22
5	Pd(OAc)2/XPhos (3/6)	4-OMe	Cs2CO3	THF/H2O (80)	83/17
6	Pd(OAc)2/1,1,3,3-tetramethylbutylisocyanide (3/6)	4-OMe	Cs2CO3	THF/H2O (80)	4/94
7	Pd(OAc)2/XPhos (3/6)	4-OMe	K2CO3	CPME/H2O (100)	100/0

^aRatio of product/starting material as determined by GC-MS assay.

Among the suite of Buchwald and other ligands examined in initial screens (Figure 1), reaction conditions developed previously in our group for the cross-coupling of aryl chlorides and -bromides with aminomethyltrifluoroborates¹⁴ proved the most efficacious for cyclopropyltrifluoroborate (entries 2–5 and 7). Thus, it was determined that 3% Pd(OAc)₂ with 6% 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos)¹⁵ as the catalyst system in the presence of a base in a 10:1 mixture of cyclopentyl methyl ether (CMPE) and H₂O (0.25 M) at 100 °C proved suitable for this reaction. In contrast to our previous reports,¹⁴ which required cesium carbonate to be used as the base, the less expensive potassium carbonate was effective in this case (entries 3 and 7). Using these reaction conditions a 75% yield of the cross coupled product (2a) was obtained from the reaction of potassium cyclopropyltrifluoroborate with 4-chloroanisole.

Figure 1.

Ligands for Cross-Coupling

We next demonstrated the substrate scope of this method. Table 2 shows the reaction of potassium cyclopropyltrifluoroborate with various aryl chlorides. Electron rich, electron poor and hindered aryl chlorides proved amenable to the reaction conditions, which tolerated numerous functional groups such as ketones, nitriles and esters. However, reduction of the nitro group to the corresponding aniline resulted when 4-chloro-1-nitrobenzene was used. This phenomenon has been observed previously in cross-coupling of organoborons with nitro-containing aryl halides.¹⁶ Highlighting the advantages of organotrifluoroborates over boronic acids and their derivatives,⁴ only 1% excess of the trifluoroborate was used in all cases.

Table 2.

Cross-Coupling of Potassium Cyclopropyltrifluoroborate with Various Aryl Chlorides^a

entry	aryl chloride	product	% isolated yield
1	1a	2a	75
2	1b	2b	82
3	1c	2c	94
4	1d	2d	90
5	1e	2e	96
6	1f	2f	76b
7	1g	2g	80b
8	1h	2h	82c

^aAll reactions used 0.5 mmol of the aryl chloride and 0.505 mmol of potassium cyclopropyltrifluoroborate.

^b10:1 THF/H₂O was used as the solvent, 80 °C.

^cReaction time was 48 h.

We next extended the method to heteroaryl chlorides, a class of electrophiles only minimally explored for the Suzuki-Miyaura reaction of cyclopropylborons.^4a Unfortunately, the reaction conditions used for aryl chlorides and several other catalyst systems (Table 3, entries 1–7) failed to afford the cross-coupled product in useful yields.

Table 3.

Optimization of Reaction Conditions for Heteroaryl Chlorides^a

entry	catalyst/ligand (mol %)	base	solvent (°C)	ratio 4a/3aa
1	Pd(OAc)2/XPhos (3/6)	K2CO3	THF/H2O (80)	72/28
2	Pd(OAc)2/XPhos (3/6)	K2CO3	CPME/H2O (100)	77/23
3	Pd(OAc)2/RuPhos (3/6)	Cs2CO3	THF/H2O (80)	46/54
4	Pd(OAc)2/DavePhos (3/6)	Cs2CO3	THF/H2O (80)	0/100
5	Pd(OAc)2/SPhos (3/6)	Cs2CO3	THF/H2O (80)	0/100
6	Pd(OAc)2/XantPhos (3/6)	Cs2CO3	THF/H2O (80)	90/10
7	Pd(OAc)2/(S)-BINAP (3/6)	Cs2CO3	THF/H2O (80)	0/100
8	Pd(OAc)2/n-BuPAd2 (3/6)	Cs2CO3	Toluene/H2O (100)	100/0

^aRatio of product/starting material as determined by GC-MS assay.

Simultaneously in our group, reaction conditions for the cross-coupling of secondary alkyltrifluoroborates, such as cyclopentyltrifluoroborate, were developed (entry 8).¹² Using these conditions [2% Pd(OAc)₂, 3% n-BuPAd₂, 3.0 equiv of Cs₂CO₃ in 10:1 toluene/H₂O at 100 °C], an 85% yield of 5-cyclopropyl-2-methoxypyridine (4a) was obtained from the reaction of 5-chloro-2-methoxypyridine with potassium cyclopropyltrifluoroborate. The scope of this reaction proved to be quite broad with respect to a wide variety of heteroaryl chlorides (Table 4).

Table 4.

Cross-Coupling of Potassium Cyclopropyltrifluoroborate with Various Heteroaryl Chlorides^a

entry	heteroaryl chloride	product	% isolated yield
1	3a	4a	85
2	3b	4b	52
3	3c	4c	95
4	3d	4d	79
5	3e	4e	70
6	3f	4f	99
7	3g	4g	90
8	3h	4h	78

^aAll reactions used 0.5 mmol of the heteroaryl chloride and 0.505 mmol of potassium cyclopropyltrifluoroborate.

Various substitution patterns and functional groups were well tolerated. Of particular interest are the 2-substituted nitrogen heterocycles, such as 2-chloroquinoline (4e) and 2-chloroquinoxaline (4d), which are sometimes difficult to couple owing to catalyst deactivation via complexation to the palladium catalyst,¹⁷ but are nevertheless desirable as substructures embedded within pharmacologically active materials.¹⁸ Notably, 4-chlorobenzonitrile and 3-chloro-4,5-dimethoxybenzonirile failed to react and afforded only starting material after 48 h by GC-MS analysis. We postulate that some interaction between the nitrile and the metal center causes the catalysts to be inactivated because the effect seems to be ligand dependent.

Finally, in an effort to expand the utility of this method for the installation of small rings into complex molecules, we synthesized cyclobutyltrifluoroborate (5) (eq 2) and subjected it to our optimized reaction conditions for cross-coupling with heteroaryl chlorides (Table 5).

Table 5.

Cross-Coupling of Potassium Cyclobutyltrifluoroborate with Various Aryl- and Heteroaryl Chlorides^a

entry	chloride	product	% isolated yield
1	6a	7a	82
2	6b	7b	74
3	6c	7c	45
4	6d	7d	63

^aAll reactions used 0.5 mmol of the aryl- or heteroaryl chloride and 0.505 mmol of potassium cyclobutyltrifluoroborate.

(2)

The reaction proved to be somewhat substrate dependent; however, it afforded aryl cyclobutanes in moderate to good yields. Unfortunately, the reaction failed to reach completion with several substrates (4-chlorobenzophenone, 5-chloro-2-thiophenecarboxaldehyde and 1-chloro-4-methoxy-2,6-dimethylbenzene). The similar physicochemical characteristics of the aryl chloride and cross-coupled products in these particular cases made effective separation by silica gel column chromatography difficult, and the desired products could not be readily isolated in pure form.

Conclusion

We have demonstrated that the palladium catalyzed Suzuki-Miyaura cross-coupling reaction can be effectively applied to the cyclopropanation of aryl chlorides. The reaction accommodates aryl- as well as heteroaryl chlorides with diverse functional groups (esters, ketones, aldehydes, nitriles) and substitution patterns. This method, in conjunction with previously developed methods for the syntheses of stereodefined cyclopropyltrifluoroborates, should find utility for the installation of cyclopropanes into a variety of functionalized aryl- and heteroaryl target molecules. Finally, suitable conditions were found for the cross-coupling of potassium cyclobutyltrifluoroborate with aryl chlorides, representing an unprecedented mode of cross-coupling reactivity.

Experimental Section

General Experimental Procedure for the Suzuki-Miyaura Cross-Coupling Reactions of Cyclopropyltrifluoroborate with Aryl Chlorides. Preparation of 1-Cyclopropyl-4-methoxybenzene (2a)

A Biotage microwave vial was charged with Pd(OAc)₂ (3.3 mg, 0.015 mmol), XPhos (14.3 mg, 0.03 mmol), potassium cyclopropyltrifluoroborate (74.7 mg, 0.505 mmol) and K₂CO₃ (210 mg, 1.5 mmol). The tube was sealed with a cap lined with a disposable Teflon septum and evacuated under vacuum and purged with N₂ three times. 4-Chloroanisole (71.3 mg, 0.5 mmol) and CPME/H₂O (10:1) (2 mL) were added by syringe and the reaction was stirred at 100 °C for 24 h, then cooled to rt and diluted with H₂O (1.5 mL). The reaction mixture was extracted with CH₂Cl₂ (3 × 5 mL). The organic layer was dried (Na₂SO₄). The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (elution with hexane/EtOAc 99:1): R_f 0.31 to yield the product as a light yellow oil in 75% yield (55.7 mg, 0.37 mmol). The spectral data match those reported in the literature.^{19 1}H-NMR (500 MHz, CDCl₃) δ: 7.01 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 1.82–1.86 (m, 1H), 0.86–0.89 (m, 2H), 0.60–0.62 (m, 2H); ¹³C-NMR (125.8 MHz, CDCl₃) δ: 157.9, 136.1, 127.1, 114.0, 55.5, 14.8, 8.6.

General Experimental Procedure for the Suzuki-Miyaura Cross-Coupling Reactions of Heteroaryl Chlorides with Potassium Cyclopropyltrifluoroborate. Preparation of 5-Cyclopropyl-2-methoxypyridine (4a)

In the glove box, a Biotage microwave vial was charged with Pd(OAc)₂ (2.2 mg, 0.01 mmol), n-BuPAd₂ (5.3 mg, 0.015 mmol), potassium cyclopropyltrifluoroborate (74.7 mg, 0.505 mmol) and Cs₂CO₃ (480 mg, 1.5 mmol). The tube was sealed with a cap lined with a disposable Teflon septum. 5-Chloro-2-methoxypyridine (71.7 mg, 0.5 mmol) and toluene/H₂O (10:1) (2 mL) were added by syringe and the reaction was stirred at 100 °C for 24 h, then cooled to rt and diluted with H₂O (1.5 mL). The reaction mixture was extracted with CH₂Cl₂ (3 × 5 mL). The organic layer was dried (Na₂SO₄). The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (elution with hexane/EtOAc 99:1): R_f 0.22 to yield the product as a light yellow oil in 85% yield (65.3 mg, 0.44 mmol). ¹H-NMR (500 MHz, CDCl₃) δ: 7.97 (s, 1H), 7.24 (dd, J = 8.5 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 3.90 (s, 3H), 1.81–1.85 (m, 1H), 0.90–0.93 (m, 2H), 0.59–0.63 (m, 2H); ¹³C-NMR (125.8 MHz, CDCl₃) δ: 162.8, 145.1, 136.6, 131.8, 110.5, 53.5, 12.4, 8.0; IR (neat) = 3006, 1608, 1495, 1286, 1025 cm⁻¹; HRMS (CI) calcd. for C₉H₁₂NO (MH⁺) 150.0919, found 150.0926.

Preparation of Potassium Cyclobutyltrifluoroborate (5)

Cyclobutylboronic acid (909 mg, 9.1 mmol) was dissolved in methanol (20 mL) at rt and the solution was cooled to 0 °C in an ice bath. A saturated aqueous solution of KHF₂ (11.1 mL) was added to the stirring solution dropwise at 0 °C. The reaction was allowed to warm to rt and stirred for an additional 3 h. The solvent was removed in vacuo and dried under vacuum overnight. The resulting crude solid was extracted three times by sonicating for 15 min and stirring for an additional 15 min in dry acetonitrile. The solvent was removed in vacuo. A minimal amount of hot acetonitrile (~50 mL) was added to dissolve the crude product and Et₂O (~150 mL) was added, leading to precipitation of the product in 63% yield as a white crystalline solid (929 mg, 5.7 mmol), which was collected by vacuum filtration and dried under vacuum. mp 200 °C (dec.). ¹H-NMR (500 MHz, Acetone-d₆) δ: 1.77–1.84 (m, 6H), 1.38 (br s, 1H); ¹³C-NMR (125.8 MHz, DMSO-d₆) δ: 23.7, 12.4; ¹⁹F-NMR (471 MHz, DMSO-d₆) δ: −144.64; ¹¹B-NMR (128.37 MHz, Acetone-d₆) δ: 4.28; IR (KBr) = 2967, 1316, 1121, 924 cm⁻¹.

General Experimental Procedure for the Suzuki-Miyaura Cross-Coupling Reactions of Aryl- and Heteroaryl Chlorides with Potassium Cyclobutyltrifluoroborate. Preparation of 1-Cyclobutyl-3, 5-dimethoxybenzene (7a)

In the glove box, a Biotage microwave vial was charged with Pd(OAc)₂ (2.2 mg, 0.01 mmol), n-BuPAd₂ (5.3 mg, 0.015 mmol), potassium cyclobutyltrifluoroborate (81.8 mg, 0.505 mmol) and Cs₂CO₃ (480 mg, 1.5 mmol). The tube was sealed with a cap lined with a disposable Teflon septum. 5-Chloro-1,3-dimethoxybenzene (86.3 mg, 0.5 mmol) and toluene/H₂O (10:1) (2 mL) were added by syringe and the reaction was stirred at 100 °C for 24 h, then cooled to rt and diluted with H₂O (1.5 mL). The reaction mixture was extracted with CH₂Cl₂ (3 × 5 mL). The organic layer was dried (Na₂SO₄). The solvent was removed in vacuo and the crude product was purified by silica gel column chromatography (elution with hexane/EtOAc 99:1): R_f 0.48 to yield the product as a light yellow oil in 82% yield (81.0 mg, 0.42 mmol). ¹H-NMR (500 MHz, CDCl₃) δ: 6.28–6.51 (m, 3H), 3.78 (s, 6H), 3.46–3.50 (m, 1H), 2.29–2.33 (m, 2H), 2.10–2.15 (m, 2H), 1.97–1.99 (m, 1H), 1.84 (m, 1H); ¹³C-NMR (125.8 MHz, CDCl₃) δ: 161.0, 149.0, 107.2, 104.6, 99.5, 97.9, 55.7, 55.4, 40.8, 29.8, 18.3; IR (neat) = 2958, 1595, 1458, 1154 cm⁻¹; HRMS (TOF) calcd. for C₁₂H₁₇O₂ (MH⁺) 193.1229, found 193.1235.

Supplementary Material

1_si_001. Supporting Information Available.

Experimental procedures, spectral characterization, and copies of ¹H, ¹³C, ¹¹B, and ¹⁹F spectra for all compounds prepared by the method described. This material is available free of charge via the Internet at http://pubs.acs.org.